Lecithinized superoxide dismutase enhances its pharmacologic potency by increasing its cell membrane affinity.
Lecithinized superoxide dismutase enhances its pharmacologic potency by increasing its cell membrane affinity.
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卵磷脂化超氧化物歧化酶通过增加其细胞膜亲和力来增强其药理效力。
DOI：
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发表时间：
1994
影响因子：
3.5
通讯作者：
Y. Mizushima
中科院分区：
文献类型：
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作者：
R. Igarashi;J. Hoshino;A. Ochiai;Y. Morizawa;Y. Mizushima
我们进行本研究是为了阐明卵磷脂化超氧化物歧化酶 (PC-SOD) 是否通过增加其细胞膜亲和力来增强其药理效力。 PC-SOD 中的 4 个磷脂酰胆碱 (PC) 衍生物分子与重组人 CuZn-SOD (rhCuZn-SOD) 的每个二聚体共价结合，使用激光共聚焦成像技术显示 PC-SOD 具有高膜亲和力。 PC-SOD 有效清除佛波醇肉豆蔻酸酯乙酸酯 (PMA) 刺激的人中性粒细胞产生的超氧阴离子 (O2-) (IC50 0.60 U/ml)，并且即使在与 PC-SOD 孵育后洗涤中性粒细胞时，它也发挥剂量依赖性的清除作用 (IC50 1.27 U/ml)。相比之下，未经修饰的 SOD 和聚乙二醇结合的 SOD (PEG-SOD) 均未表现出对洗涤的中性粒细胞的清除作用，即使在高浓度 (100 U/ml) 下也是如此。 PC-SOD 还对受刺激的中性粒细胞产生的 O2- 引起的人血管内皮细胞损伤显示出强大的保护作用，并且 PC-SOD 的效力比未修饰的 SOD 强约 100 倍（PC-SOD 的体外 IC50 为 100 U/ml，未修饰的 SOD 的体外 IC50 > 10,000 U/ml）。此外，PC-SOD（50,000 U/kg）对小鼠缺血再灌注爪水肿有抑制作用，而未修饰的SOD和PEG-SOD均没有任何作用。这些结果表明，PC-SOD（旨在靶向细胞膜）通过增加细胞膜亲和力比未修饰的 SOD 发挥了更高的药理活性，并且可能具有潜在的各种临床应用价值。
We performed the present study to clarify whether lecithinized superoxide dismutase (PC-SOD) enhanced its pharmacologic potency by increasing its cell membrane affinity. PC-SOD, in which 4 molecules of a phosphatidylcholine (PC) derivative were covalently bound to each dimer of recombinant human CuZn-SOD (rhCuZn-SOD), was shown to have a high membrane affinity using a laser confocal imaging technique. PC-SOD efficiently scavenged superoxide anion (O2-) produced by phorbol myristate acetate (PMA)-stimulated human neutrophils (IC50 0.60 U/ml), and it exerted a dose-dependent scavenging effect (IC50 1.27 U/ml) even when the neutrophils were washed after incubation with PC-SOD. In contrast, neither unmodified SOD nor polyethylene glycol-bound SOD (PEG-SOD) showed a scavenging effect for washed neutrophils, even at a high concentration (100 U/ml). PC-SOD also showed a strong protective effect against human vascular endothelial cell damage caused by O2- generated by stimulated neutrophils, and PC-SOD was approximately 100-fold more potent than unmodified SOD (in vitro IC50 100 U/ml for PC-SOD and > 10,000 U/ml for unmodified SOD). Moreover, PC-SOD (50,000 U/kg) had an inhibitory effect on ischemia-reperfusion paw edema in mice, whereas neither unmodified SOD nor PEG-SOD had any effect. These results suggest that PC-SOD (designed to target for cell membranes) exerted a far higher pharmacologic activity by increasing cell membrane affinity than unmodified SOD and may be potentially useful for various clinical applications.